Galanin-like peptide (GALP) is a newly discovered member of the galanin family of neuropeptides. GALP shares a partial sequence homology with galanin; however, GALP is coded by a separate gene and is likely to have its own unique receptor. Work from our laboratory and others has shown that the expression of GALP mRNA in the brain is limited to a cluster of neurons in the hypothalamic arcuate nucleus and the median eminence. We have recently discovered that GALP neurons are direct targets for the adipocyte-derived hormone leptin. The expression of GALP mRNA is reduced in leptin-deficient states, which can be reversed by the concomitant administration of leptin. When administered into the brain, GALP produces a dose-dependent inhibition of feeding and body weight and also stimulates luteinizing hormone (LH) and testosterone secretion. These studies suggest that GALP neurons serve as part of the hypothalamic circuitry linking the regulation of body weight and reproduction; however, beyond these observations, we understand little about GALP's physiological importance. We propose to use neuroanatomical, pharmacological, and molecular biological techniques to reveal the anatomical circuitry governing GALP cells, map their projections, and discern GALP's functional significance. Our primary aims are 1) to examine the effects of leptin, insulin and ghrelin on GALP neurons and characterize the synaptic inputs and molecular physiology of these cells-focusing on inputs from NPY, proopiomelanocortin, and serotonin, as well as on key transcription factors; 2) to identify the targets of GALP projections in the brain and to reveal its signaling mechanisms; and 3) to assess the functional significance of GALP by evaluating mice with a targeted deletion of the GALP gene, examining the role of GALP in mediating the effects of leptin on the neuroendocrine reproductive axis, and evaluating the functional significance of NPY inputs to GALP neurons, particularly in the context of gonadotropin secretion. Learning the basic circuitry that couples GALP to other neuronal systems, understanding more about the molecular physiology of GALP neurons, establishing the cellular, molecular, and physiological effects of GALP, and learning how GALP neurons are regulated by metabolic hormones are fundamental to understanding GALP's functional role in the orchestration of the neuroendocrine reproductive system, as well as other important physiological processes. [unreadable] [unreadable]